Studying the logic of small neural circuits is an essential step toward understanding more complex circuits and, ultimately, the computational and integrative properties of whole nervous systems. With a compact nervous system (just 302 neurons) and a well-characterized behavioral repertoire, the small roundworm C. elegans serves as an excellent animal model to study circuit-level modulation of neuronal function. While chemical synapses allow neurons to communicate with each other through the vesicular release of neurotransmitters into synaptic clefts between the cells, gap junctions allow for direct cytoplasmic communication and electrical coupling between neurons. As such, gap junctions are often referred to as electrical synapses. Importantly, the presence of gap junctions in the nervous system allows for the establishment of even more complex circuits than can be generated by synaptic signaling alone. We have identified a non-cell-autonomous role for guanylyl cyclases in the regulation of nociceptive sensory behaviors, and have gathered evidence for circuit-level modulation of neuronal activity by movement of the second messenger cGMP through gap junctions. As an important step towards our long-term goal of understanding how cellular and intercellular mechanisms interact within neural circuits to control animal behavior, the overall objective of this application is to determine the mechanism by which select guanylyl cyclases modulate nociceptive behavioral responses in C. elegans. Herein we propose to use a combination of genetic, behavioral and neuronal imaging approaches in C. elegans to establish how cGMP generation and movement through gap junctions regulates nervous system function. We will: (1) use in vivo imaging to characterize cGMP and Ca2+ dynamics in a sensory neural circuit, (2) determine the mechanism by which specific guanylyl cyclases modulate ASH nociceptor sensitivity non-cell-autonomously, and (3) define the network(s) of gap junction components that coordinate to pass cGMP to modulate ASH nociceptor sensitivity. Together, these studies will delineate a new means of neuronal communication and a new mechanism for the coordination and optimization of animal behavior. This information is required to develop innovative pharmacological approaches to modulate gap junction signaling for therapeutic goals.